Compositions containing omega-3 oil and uses thereof

ABSTRACT

The invention provides pharmaceutical compositions containing omega-3 oil and a non-hydrophilic co-solvent that have an increased absorption rate. The pharmaceutical compositions may further contain one or more pharmaceutical organic molecules. The invention further provides kits containing these pharmaceutical compositions, methods for formulating pharmaceutical compositions containing omega-3 oil, and methods for decreasing the likelihood of developing cardiovascular disease, decreasing triglyceride or LDL cholesterol levels, decreasing pain or inflammation, treating diabetes, chronic pulmonary diseases, or irritable bowel syndrome, decreasing symptoms of an autoimmune disease or allergic conditions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.13/822,517, filed Apr. 12, 2013, which is the U.S. National Stage ofInternational Application No. PCT/US2011/51698, filed Sep. 15, 2011,which claims benefit of U.S. Provisional Application No. 61/383,972,filed Sep. 17, 2010, each of which is hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to the field of pharmacology and molecularmedicine. More specifically, the invention relates to pharmaceuticalcompositions containing omega-3 oil in co-solvents that are useful fortreating, e.g., cardiovascular conditions, and/or as vehicles fordelivering other therapeutic agents.

BACKGROUND OF THE INVENTION

Omega-3 oil is widely regarded as having certain therapeutic benefitsprimarily associated with cardiovascular disease. As the scientificcommunity has become more comfortable with the safety and efficacy ofomega-3 oils, the recommended daily dose has risen from less than a gramper day to over 8 grams per day. Omega-3 oils are essentially non-toxicand doses exceeding 20 grams per day have been taken over prolongeddosing periods without side effects. As high doses and highconcentrations of omega-3 oils are required for therapeutic benefit,processes to enhance the absorption of omega-3 oil, to decrease theabsorption time, and to increase the maximum peak concentration achievedin human blood are desired.

Desirable omega-3 oil compositions must contain high concentrations ofthe established active therapeutic fatty acids: eicosapentaenoic acid(EPA) and docosahexanoic acid (DHA). Omega-3 oil compositions shouldalso be rapidly absorbed so that EPA and DHA can compete effectivelywith other fatty acids (e.g., omega-6 fatty acids) for integration andstorage in cell membranes and in tissue triglyceride storage forms,which later are broken down to provide free EPA and DHA. Currentpractice suggests the use of liquid formulations containing, minimally3.5 grams of active oil (combined EPA and DHA) in a reasonable volumefor ingestion (e.g., 10 mL). For patients to comply with a once-a-dayregime, the oil must have an acceptable taste and induce little or nonausea, intestinal discomfort, or regurgitation.

Based on current literature, the optimal dose of EPA and DHA isapproximately 4 grams per day given at a single dosing. It is difficultto ingest enough gel capsules to achieve this dosage. Compliance andswallowing difficulties limit the ability of many patients fromconsistently taking an amount of omega-3 oil sufficient to elicit atherapeutic effect. High grade liquid oils are available that allowpatients to take these quantities of oils, but the dose volume, taste,and costs are negative factors. Costs become prohibitive whenchemically-altered or refined omega-3 oils from the natural state areused. The weakness in the available oil products is that thesecompositions have not been optimized for absorption.

High grade omega-3 oils, such as Maine Natural Health's OmegaMaineproduct lines, Nordic Naturals liquid formulations, and Carlsson liquidomega-3 product, are presently available. Of these products, MaineNatural Health's product is the only product that can deliver 3.5 gramsof active combined EPA and DHA in a volume as little as 10 mL. Reducingthe volume of the unit dose required for therapeutic benefit willincrease patient compliance (especially in patients having dysphagia).The optimal unit dosage may be dispensed in an easy to administervolume, e.g., 2 teaspoons or 10 mL. Despite the high quality of omega-3oil contained within these products, the absorption efficiencies (timeto maximum plasma concentration, t^(1/2) for absorption) of the productsare not optimal. It is desirable to achieve high initial plasmaconcentrations to optimize the incorporation of the active omega-3 oilsinto cell membrane lipid bilayers and triglyceride stores.

The other marketed omega-3 products are also not optimized forabsorption. Omacor or Lovaza is the only FDA-approved ethyl esterderivative of EPA. It is prescribed for patients with very hightriglycerides and is administered in four large gel caps on a dailybasis. When taken by oral ingestion, these large gel caps are dissolved(dissolution rate dependent step), de-esterified to fatty acids, andthen absorbed. The conditions for dissolution and absorption are notoptimal for these products, and thus, the efficiency of integration intocell membranes and triglyceride storage forms is not optimal.

Dietary supplements containing omega-3 oils, formulated as both gel capsand liquid formulations, are also available. The gel caps are inferiorto Lovaza/Omacor (described above) and also suffer from a reducedefficiency of absorption. Thus, compositions containing omega-3 oilswith improved efficiency of absorption are needed.

SUMMARY OF THE INVENTION

In a first aspect, the invention provides compositions containingomega-3 oil in a non-hydrophilic co-solvent containing an herbal-basedoil, vitamin E, medium chain triglycerides (MCTs), lecithin, andphosphatidylcholine. Any of the compositions described herein may beformulated as a liquid (e.g., formulated for oral administration). Inthe provided compositions, the omega-3 oil may be from a natural source(e.g., salmon, herring, mackerel, and sardines), may be high grade(e.g., OmegaMaine omega-3 oils), may be an alkyl ester of a fatty acid(e.g., an alkyl ester of EPA and/or an alkyl ester of DHA), may be inthe form of triglycerides, and/or may be a mixture of triglycerides andfree fatty acids. In certain embodiments, the provided compositions areformulated in a dose containing greater than 3.0 g combined EPA and DHAin 10 mL (e.g., in a liquid formulation). In different embodiments ofthe above compositions, the non-hydrophilic co-solvent is less than 30%of the composition's total mass, the herbal-based oil (e.g., rosemaryoil, basil oil, turmeric oil, and ginger oil) is 1% to 10% of thecomposition's total mass (e.g., between 3% to 5% of the composition'stotal mass), and/or amount of vitamin E present in a single dose isbetween 13.4 to 134 mg or is 1.3% to 13.4% of the composition's totalmass.

In any of the above compositions, the MCTs (e.g., MCTs from coconut oil)are between 1% to 10% (e.g., 5%) of the composition's total mass and/orthe phosphatidylcholine is 2% to 6% of the composition's total mass.Additional embodiments of the above compositions may further contain oneor more nitric oxide-stimulating or -releasing agent(s) (e.g., arginine,a di-arginine, and citrulline), glucosamine, ethanol, and/or a Tweensurfactant (e.g., Tween-80, Tween-60, Tween-40, and Tween-20). Forexample, any of the above compositions may contain rosemary oil andglucosamine, or may contain ethanol and Tween surfactant.

Additional embodiments of the above compositions may further contain oneor more therapeutic organic molecule(s) (e.g., a NSAID, such asketoprofen, ibuprofen, diflusinal, diclofenac, and naproxen), a DMARD(e.g., methotrexate), fenofibrate, a statin, niacin, and/or a H-1antihistamine) with a molecular weight between 100 g/mole and 800g/mole, a log P value greater than 2, or a melting point below 200° C.Such compositions containing one or more therapeutic organic molecule(s)may further contain ethanol and a Tween surfactant. For example, a doseof any of the above compositions may contain 5 mg/mL to 20 mg/mL (10mg/mL to 15 mg/mL) fenofibrate and/or 1 mg/mL to 4 mg/mL of a statin(e.g., 0.5 mg/mL to 2 mg/mL of a statin). In various embodiments, theabove compositions may further contain a DMARD, a NSAID, rosemary oil,and/or glucosamine. In additional examples of the above compositions,the H-1 antihistamine is from the tricyclic class of antihistamines(e.g., imipramine and doxepin) or from the non-tricyclic class ofantihistamines (e.g., diphenhydramine and triprolidine).

Any of the above compositions may further contain one or more agentsselected from: phosphatidylcholine, phosphatidylethanolamine,phosphatidylinositol, and phosphatidic acid. For example, a compositionof the invention may contain phosphatidylinositol and phosphatidic acid.In additional embodiments of the compositions, 10% of the omega-3 oil isin solution and the remaining 90% of the omega-3 oil is in stablesuspension form.

In one embodiment, the composition contains: 70% to 80% w/w of naturalfish oil as a source of omega-3 oil; 5% to 15% w/w coconut oil as asource of MCTs; 0.5% to 5% w/w polytocopherol as a source of vitamin E;1% to 10% w/w absolute ethanol; 1% to 10% w/w sorbital laurate; and 1%to 10% w/w cremaphor. In another embodiment, the composition contains:70% to 80% w/w natural fish oil as a source of omega-3 oil; 5% to 15%w/w coconut oil as a source of MCTs; 0.5% to 5% w/w polytocopherol as asource of vitamin E; 1% to 5% w/w absolute ethanol; and 5% to 15%cremaphor.

In a further embodiment, the composition contains: 65% to 75% w/w ofnatural fish oil as a source of omega-3 oil; 1% to 10% w/w of coconutoil as a source of MCTs; 0.5% to 5% w/w polytocopherol as a source ofvitamin E; 1% to 10% w/w absolute ethanol; 1% to 10% w/w sorbitallaurate; 1% to 10% w/w cremaphor; and 1% to 10% w/w of a therapeuticorganic molecule. In another embodiment, the composition contains: 65%to 75% w/w of natural fish oil as a source of omega-3 oil; 1% to 10% ofcoconut oil as a source of MCTs; 0.5% to 5% w/w polytocopherol as asource of vitamin E; 1% to 5% w/w absolute ethanol; 1% to 10% w/wsorbital laurate; 1% to 15% cremaphor; and 1% to 10% w/w of atherapeutic organic molecule.

The invention further provides kits containing one or more of the abovecompositions and instructions for administering these composition(s) toa subject. In various embodiments, the kits may further contain at leastone additional composition containing a NSAID, a DMARD, or an H-1antihistamine. In various embodiments of these kits, the additional H-1antihistamine is from the tricyclic class of antihistamines (e.g.,imipramine or doxepin) or is from the non-tricyclic class ofantihistamines (e.g., diphenhydramine or tripolidine).

The invention further provides methods of decreasing the likelihood ofdeveloping a cardiovascular disease by administering to a subject any ofthe above compositions for a time and in an amount to reducetriglyceride or low-density lipoprotein (LDL) cholesterol levels in theblood of the subject, or to increase the amount of omega-3 oil presentin the cell membranes of red blood cells in the subject. In variousembodiments of these methods, the composition (e.g., formulated as aliquid) is administered once a day (e.g., orally administered, such asin the form of a liquid). In various embodiments of the methods, thecomposition is administered in a dose containing greater than 3.0 gcombined EPA and DHA in 10 mL.

Desirably, the administering of one or more of the above composition(s)results in at least a 10% decrease in triglyceride or LDL cholesterollevels in the blood of the subject, at least a 10% increase in theamount of omega-3 oil present in the cell membranes of red blood cellsin the subject, at least a 5% decrease in blood pressure in the subject,and/or a reduction in nausea or esophageal reflux compared to the nauseaor esophageal reflux observed following administration of omega-3 oilsalone.

The invention further provides methods for decreasing the triglycerideor low-density lipoprotein (LDL) cholesterol levels in a subject byadministering one or more of the above composition(s) to the subject. Invarious embodiments of these methods, the composition (e.g., formulatedas a liquid) is administered once a day (e.g., orally administered, suchas in the form of a liquid). In various embodiments of the methods, thecomposition is administered in a dose containing greater than 3.0 gcombined EPA and DHA in 10 mL.

Desirably, the administering of one or more of the above composition(s)results in at least a 10% decrease in triglyceride or LDL cholesterollevels in the blood of the subject, at least a 10% increase in omega-3oil present in the cell membranes of red blood cells in the subject,and/or results in a reduction in nausea or esophageal reflux compared tothe nausea and esophageal reflux observed following administration ofomega-3 oils alone.

In another aspect, the invention provides methods of treating diabetescomprising administering one or more of the above composition(s) for atime and in an amount sufficient to increase insulin sensitivity in thesubject or increase high density lipoprotein (HDL) cholesterol levels inthe blood of the subject. In various embodiments of these methods, thecomposition administered contains phosphatidylinositol, phosphatidicacid, phosphatidylethanolamine, and/or phosphatidylserine (e.g.,phosphatidylinositol and phosphatidic acid). In additional embodimentsof these methods, the composition (e.g., formulated as a liquid) isadministered once a day (e.g., orally administered, such as in the formof a liquid). In further embodiments of these methods, the compositionis administered in a dose containing greater than 3.0 g combined EPA andDHA in 10 mL.

Desirably, the administering of one or more of the above composition(s)results in at least a 10% increase in insulin sensitivity in the subjector at least a 10% increase in HDL cholesterol levels in the blood of thesubject.

The invention also provides methods of decreasing pain or inflammationin a subject by administering one or more of the above composition(s) toa subject. In various embodiments of these methods, the compositioncontains an NSAID and/or a DMARD, or rosemary oil and glucosamine. Invarious embodiments of these methods, the composition (e.g., formulatedas a liquid) is administered once a day (e.g., orally administered, suchas in the form of a liquid). In various embodiments of the methods, thecomposition is administered in a dose containing greater than 3.0 gcombined EPA and DHA in 10 mL. In different embodiments of thesemethods, the one or more above composition(s) is administered at thesame time as a NSAID or a DMARD, or is administered prior to a NSAID ora DMARD.

Desirably, the administering of one or more of the above composition(s)results in at least a 5% reduction in pain score, at least a 5%reduction in cyclooxygenase (COX)-1 or COX-2 activity, at least a 5%reduction in white blood cell count, or at least a 5% reduction inC-reactive protein, interleukin-6, and/or TNF-α levels, at least a2-fold decrease in the time to optimal therapeutic effect, and/or theformation of less gastric lesions than administration of a NSAID or aDMARD alone.

In another aspect, the invention provides methods of treating a chronicpulmonary disease (e.g., asthma and chronic obstructive pulmonarydisease) or irritable bowel syndrome, or reducing one or more symptomsof an autoimmune disease (e.g., multiple sclerosis and lupuserythematosus) by administering to the subject one or more of the abovecomposition(s). In additional embodiments of these methods, thecomposition further contains a NSAID, a DMARD, rosemary oil, and/orglucosamine. In various embodiments of these methods, the compositioncontains an NSAID and/or a DMARD, or rosemary oil and glucosamine. Inadditional embodiments of these methods, the composition (e.g.,formulated as a liquid) is administered once a day (e.g., orallyadministered, such as in the form of a liquid). In further embodimentsof these methods, the composition is administered in a dose containinggreater than 3.0 g combined EPA and DHA in 10 mL. In examples of thesemethods, the one or more composition(s) is administered at the same timeas an NSAID or a DMARD, or is administered prior to a NSAID or a DMARD.

Desirably, these methods result in at least a 2-fold decrease in thetime to optimal therapeutic effect or result in less gastric lesionsthan administration of a NSAID or a DMARD alone.

The invention further provides methods of formulating an omega-3oil-containing pharmaceutical compositions having at least a 10%increase in absorption rate relative to the absorption rate of omega-3oil alone, requiring the step of combining an omega-3 oil with aco-solvent containing one or more solvents or agents selected from thegroup of: a herbal-based oil, vitamin E, MCTs, lecithin,phosphatidylcholine, glucosamine, ethanol, a Tween surfactant,phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol,phosphatidic acid, natural fish oil, coconut oil, polytocopherol,sorbital laurate, and cremaphor. In certain embodiments of thesemethods, the co-solvent contains a herbal-based oil, vitamin E, MCTs,lecithin, and phosphatidylcholine. In additional embodiments of thesemethods, the co-solvent contains natural fish oil, coconut oil,polytocopherol, sorbital laurate, cremaphor, an amide of an intermediate(C-6 to C-12) chain fatty acid, an amide of a long chain (C-12 to C-24fatty acid), lauric alcohol, and lauric acid.

The invention also provides methods of formulating a pharmaceuticalcomposition containing omega-3 oil and one or more therapeutic organicmolecule(s) having at least a 10% increase in absorption rate relativeto the absorption rate of omega-3 oil alone or the one or moretherapeutic organic molecule(s) alone, requiring the step of combiningan omega-3 oil and one or more therapeutic organic molecule(s) with aco-solvent containing one or more solvents or agents selected from thegroup of: a herbal-based oil, vitamin E, MCTs, lecithin,phosphatidylcholine, glucosamine, ethanol, a Tween surfactant,phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol,phosphatidic acid, natural fish oil, coconut oil, polytocopherol,sorbital laurate, cremaphor, an amide of an intermediate (C-6 to C-12)chain fatty acid, an amide of a long chain (C-12 to C-24 fatty acid),lauric alcohol, and lauric acid. In various examples of these methods,the co-solvent contains a herbal-based oil, vitamin E, MCTs, lecithin,and phosphatidylcholine. In additional examples of these methods, theco-solvent contains natural fish oil, coconut oil, polytocopherol,absolute ethanol, sorbital laurate, and cremaphor. In additionalexamples of these methods, the one or more therapeutic organicmolecule(s) are first combined with the co-solvent to solubilize the oneor more therapeutic organic molecule(s), and then omega-3 oil is addedto form the pharmaceutical composition.

In further examples of these methods, the composition contains ethanol(e.g., contains ethanol, a Tween surfactant (e.g., Tween-80), MCTs,vitamin E, and lecithin).

By the term “omega-3 oil” is meant an oil that contains at least one(e.g., one, two, or three) fatty acid(s) containing a carbon-carbondouble bond in the n-3 position (i.e., the third bond from the methylend of the fatty acid). Non-limiting examples of fatty acids that may bepresent in an omega-3 oil include: all-cis-7,10,13-hexadecatrienoicacid; α-linolenic acid (ALA) (all-cis-9,12,15-octadecatrienoic acid);stearidonic acid (SDA) (all-cis-6,9,12,15-octadecatetraenoic acid);eicosatrienoic acid (ETE) (all-cis-11,14,17-eicosatrienoic acid);eicosatetraenoic acid (ETA) (all-cis-8,11,14,17-eicosatetraenoic acid);eicosapentaenoic acid (EPA) (all-cis-5,8,11,14,17-eicosapentaenoicacid); docosapentaenoic acid (DPA)(all-cis-7,10,13,16,19-docosapentaenoic acid); docosahexaenoic acid(DHA) (all-cis-4,7,10,13,16,19-docosahexaenoic acid);tetracosapentaenoic acid (all-cis-9,12,15,18,21-tetracosapentaenoicacid); and tetracosahexaenoic acid (nisinic acid)(all-cis-6,9,12,15,18,21-tetracosahexaenoic acid).

Natural sources of omega-3 oils include, but are not limited to, coldwater oily fish e.g., salmon, tuna, herring, mackerel, anchovies, andsardines), pollock, cod, catfish, flounder, grouper, halibut, mahi mahi,orange roughy, red snapper, shark, swordfish, tilefish, plankton, algae,krill, green-lipped mussel, chia seeds, kiwifruit seeds, perilla seeds,flax seeds, lingonberry seeds, camelina seeds, purslane seeds, blackraspberry seeds, hemp seeds, butternut, walnuts, pecan nuts, and hazelnuts.

By the term “herbal-based oil” is meant an oil extracted from a herbplant (e.g., rosemary, basil, turmeric, and ginger). The herbal-basedoil may inhibit cyclooxgenase COX-1 or COX-2 activity (e.g., mediate atleast a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%,90%, or 95% decrease in COX-1 and/or COX-2 activity). These herbal oilscontain mixtures of low potency cyclooxygenase (COX-1 and/or COX-2)inhibitors. These multi-component mixtures are additive in theireffects. They are also synergistic because the various molecularinhibitors act/bind to different molecular sites on the enzyme (i.e.,COX-1 and/or COX-2) surface and change the intrinsic ability of theseenzymes to function. Multiple site inhibitors make these oils effectiveas therapeutic agents. Final concentrations of herbal extract inpharmaceutical compositions between 1% and 10% (by weight) are optimal.Combinations of multiple (e.g., two, three, four, or five) herbals oilsare useful and provide greater efficacy.

By the term “high grade omega-3 oil” is meant an omega-3 oil preparationthat is substantially free of impurities (e.g., at least 70%, 75%, 80%,85%, 90%, 95%, 96%, 97%, 98%, or 99% pure). For example, a high gradeomega-3 oil may be purified to remove vitamin A, vitamin D, mercury,lead, polychlorinated biphenyls, and dioxins.

By the term “nitric oxide-stimulating or -releasing agent” is meant amolecule that stimulates nitric oxide production from a nitric oxidesynthetase (NOS) (e.g., endothelial NOS, inducible NOS, and neuronalNOS) or a molecule that releases nitric oxide (e.g., natural degradationor enzyme-mediated degradation). A non-limiting example of a moleculethat stimulates nitric oxide production is citrulline. Non-limitingexamples of molecules that break down to release nitric oxide includearginine, di-arginine, nitroglycerin, organic nitrates (e.g., glyceryltrinitrate, isosobride dinitrate, and isosorbide-5-mononitrate), sodiumnitroprusside, S-nitrosothiols (e.g., S-nitroso-N—N-acetylpenicillamineand S-nitrosoglutathione), sydnonimines (e.g., molsidomine and3-morpholino-sydnonimine), NONOates (e.g., spermine NONOate), andfuroxans.

By the term “Tween surfactant” is meant a nonionic detergent derived inpart from polyethoxylated sorbitan. Non-limiting examples of Tweensurfactants include Tween-20, Tween-40, Tween-60, and Tween-80.

By the term “non-steroidal anti-inflammatory drug” or “NSAID” is meant anon-steroidal agent that prevents or diminishes inflammation. NSAIDsinclude naproxen sodium, diclofenac sodium, diclofenac potassium,aspirin, sulindac, diflunisal, piroxicam, indomethacin, ibuprofen,nabumetone, choline magnesium trisalicylate, sodium salicylate,salicylsalicylic acid, fenoprofen, flurbiprofen, ketoprofen,meclofenamate sodium, meloxicam, oxaprozin, sulindac, tolmetin, andCOX-2 inhibitors such as rofecoxib, celecoxib, valdecoxib, orlumiracoxib.

By the term “disease-modifying anti-rheumatic drug” or “DMARD” is meanta therapeutic agent used for the treatment of an inflammatory disease.Examples of DMARDs known in the art include, e.g., auranofin,aurothioglucose, azathioprine, chlorambucil, cyclophosphamide,D-penicillamine, gold sodium thiomalate (injectable gold),hydroxychloroquine, leflunomide, methotrexate, minocycline,mycophenolate mofetil, and sulfasalazine.

By the term “therapeutic organic molecule” is meant a molecule that maybe used to reduce the likelihood (e.g., at least a 5%, 10%, 15%, 20%,25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 95% reduction) ofdeveloping a disease or to treat or ameliorate one or more symptoms of adisease in a subject (e.g., reduce the severity of one, two, three,four, or five symptoms by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 60%, 70%, 80%, 90%, or 95%). A therapeutic organicmolecule may have a molecular weight between 100 g/mole and 800 g/mole,a log P value greater than 2, or a melting point of below 200° C. Inaddition, therapeutic organic molecules may be soluble in a hydrophobicenvironment (e.g., a solvent). Non-limiting examples of therapeuticorganic molecules include NSAIDs (e.g., ketoprofen), DMARDs (e.g.,methotrexate), fenofibrate, a statin, and niacin.

By the phrase “decreasing the likelihood of developing” is meant areduction (e.g., at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%,60%, 70%, 80%, 90%, or 95%) for a subject or a patient population in thechance or rate of developing a specific disease (e.g., cardiovasculardisease) by administering one or more pharmaceutical compositionscompared to a subject or patient population not receiving the one ormore pharmaceutical compositions. The methods of the invention may alsoreduce the likelihood of developing one or more (e.g., one, two, three,four, or five) symptoms of a disease (e.g., cardiovascular disease ordiabetes) in a patient population or a subject receiving one or more ofthe provided pharmaceutical compositions.

By “treating” a disease in a subject is meant reducing the severity orduration of at least one symptom (e.g., one, two, three, four, or fivesymptoms) of the disease by administrating one or more pharmaceuticalcomposition(s) to the subject.

By the phrase “one or more symptoms of cardiovascular disease” is meantone or more symptoms clinically observed for patients havingcardiovascular disease. Non-limiting examples of symptoms ofcardiovascular disease include: shortness of breath, heart palpitations,increased heart rate, increased blood pressure, weakness, dizziness,nausea, sweating, atherosclerotic plaques in artery walls, elevatedlow-density lipoprotein (LDL) cholesterol levels (e.g., greater than 70mg/dL, 100 mg/dL, 130 mg/dL, 150 mg/dL, or 200 mg/dL), decreasedhigh-density lipoprotein (HDL) cholesterol levels (e.g., less than 50mg/dL or less than 40 mg/dL), and increased triglyceride levels (e.g.,greater than 150 mg/dL).

By the phrase “one or more symptoms of diabetes” is meant one or moresymptoms clinically observed for patients having diabetes (e.g., type Idiabetes, type II diabetes, or pre-diabetes). Non-limiting examples ofsymptoms of diabetes include: frequent urination, unusual thirst,extreme hunger, unusual weight loss, extreme fatigue and irritability,frequent infections, blurred vision, tingling/numbness in extremities,recurring infections (e.g., skin, gum, and bladder infections),decreased insulin absorption or sensitivity (e.g., decrease by at least10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%), elevatedblood glucose levels (e.g., one or more blood glucose readings ofgreater than 104 mg/dL), and increased glycated hemoglobin levels (e.g.,HbA_(1C) greater than 7.0%).

By the phrase “decreasing the triglyceride or low-density lipoproteincholesterol levels” is meant a reduction of at least 5% (e.g., at least10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70%) inthe triglyceride levels or LDL cholesterol levels in a subject comparedto the triglyceride or LDL cholesterol levels in the subject prior totreatment or a subject or patient population not receiving therapeutictreatment. For a human, the normal triglyceride level is <150 mg/dL andthe normal LDL cholesterol level is 25 mg/dL to <70 mg/dL. A decrease intriglyceride level may result in a reduction of an elevated triglyceridelevel (e.g., greater than or equal to 150 mg/dL) to a triglyceride levelwithin the normal range (e.g., less than 150 mg/dL). A decrease in LDLcholesterol level may result in a reduction of an elevated LDLcholesterol level (e.g., greater than or equal to 70 mg/dL or greaterthan or equal to 100 mg/dL) to a LDL cholesterol level within the normalrange (e.g., 25 mg/dL to <70 mg/dL).

By the term “diabetes” is meant both type I diabetes (juvenile-onset ordiabetes mellitus) and type II diabetes (adult-onset diabetes). The termdiabetes is also meant to include those individuals designated as being“pre-diabetic” or indicated as having a propensity to develop type IIdiabetes based on the presentation of one or more (e.g., one, two,three, or four) of the following symptoms: increased weight (obesity),decreased insulin absorption or sensitivity (e.g., decrease by at least5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%), elevatedblood glucose levels (e.g., one or more blood glucose readings greaterthan 104 mg/dL), and increased glycated hemoglobin levels (e.g.,HbA_(1C) greater than 7.0%). Treatment of diabetes may result in anincrease (e.g., by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 70%, 80%, 90%, or 95%) in insulin absorption orsensitivity, a decrease (e.g., by at least 5%, 10%, 15%, 20%, 25%, 30%,35%, 40%, 45%, 50%, 55%, or 60%) in blood glucose levels in a subject orpatient population having elevated blood glucose (e.g., one or moreblood glucose readings greater than 104 mg/dL), and a decrease (e.g., byat least 5%, 10%, 15%, 20%, 25%, or 30%) in glycated hemoglobin levelsin a subject or patient population having increased glycated hemoglobinlevels (e.g., HbA_(1C) greater than 7.0%).

By the term “decreasing pain in a subject” is meant a decrease (e.g., atleast 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,70%, 80%, 90%, or 95%) in the pain score of a subject or patientpopulation receiving therapeutic treatment compared to the pain score ofa subject or patient population prior to treatment or the pain score ofa subject or patient population not receiving the therapeutic treatment.Non-limiting examples of tests to quantify pain in a subject include:Alder Hey Triage Pain Score, Brief Pain Inventory (BPI), Dallas PainQuestionnaire, Dolorimeter Pain Index (DPI), Faces Pain Scale-Revised(FPS-R), Face Legs Arms Cry Consolability scale, McGill PainQuestionnaire (MPQ), Descriptor Differential Scale (DDS), Neck Pain andDisability Scale (NPAD), Numerical 11 point box (BS-11), Numeric RatingScale (NRS-11), Roland-Morris Back Pain Questionnare, Wong-Baker FACESPain Rating Scale, and Visual Analog Scale (VAS). A decrease in pain mayresult in at least a 5% decrease (e.g., at least a 10%, 15%, 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 80%, 90%, or 95% decrease) inone or more (e.g., one, two, three, or four) of the pain scores listedabove.

By the term “decreasing inflammation in a subject” is meant a decrease(e.g., at least 5%, 10%, 15%, 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%,65%, 70%, 80%, 90%, or 95% decrease) in the severity or duration of oneor more symptoms (e.g., one, two, three, four, or five symptoms) ofinflammation in a subject receiving treatment compared to the severityor duration of one or more symptoms of inflammation in the subject priorto treatment or the severity or duration of one or more symptoms ofinflammation in a subject or patient population not receivingtherapeutic treatment. Non-limiting examples of symptoms of inflammationinclude: increased (e.g., by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, 60%, 70%, 80%, 90%, or 95%) COX-1 and/or COX-2activity, increased (e.g., by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, 60%, 70%, 80%, 90%, or 95%) white blood cell count,increased (e.g., by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 70%, 80%, 90%, or 95%) C-reactive protein, interleukin-6,and/or TNF-alpha levels, swelling, pain, and increased (e.g., by atleast 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%,80%, 90%, or 95%) erythrocyte sedimentation rate. The methods of theinvention may result in a reduction (e.g., by at least 5%, 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 80%, 90%, or 95%) inCOX-1 and/or COX-2 activity, a decrease (e.g., by at least 5%, 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 80%, 90%, or 95%) inthe white blood cell count, a decrease (e.g., by at least 5%, 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 80%, 90%, or 95%) inC-reactive protein levels, decreased swelling, decreased pain (e.g, atleast a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%,90%, or 95% decrease in one or more (e.g., one, two, three, four, orfive) of the pain scores listed above), and a decrease (e.g., by atleast 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%,80%, 90%, or 95%) in erythrocyte sedimentation rate.

By “symptoms of autoimmune disease” is meant one or more symptomsclinically observed for patients having an autoimmune disease (e.g.,multiple sclerosis and lupus erythematosus). Non-limiting examples ofsymptoms of autoimmune disease include pain (e.g., joint pain),inflammation, and loss of motor function.

The recitation herein of numerical ranges by endpoints is intended toinclude all numbers subsumed within that range (e.g., a recitation of 1to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5).

As used herein, “a” or “an” means “at least one” or “one or more” unlessotherwise indicated. In addition, the singular forms “a”, “an” and “the”include plural referents unless the context clearly dictates otherwise.Thus, for example, reference to a composition containing “a compound”includes a mixture of two or more compounds.

Other features and advantages of the invention will be apparent from thefollowing description of the preferred embodiments thereof, and from theclaims.

DETAILED DESCRIPTION

We have discovered a new method for formulating compositions containingomega-3 oils that allow for an increased rate of absorption in mammals(e.g., humans). The invention therefore provides compositions containingomega-3 oils that exhibit increased absorption rates, kits containingthese compositions, and methods for decreasing the likelihood ofdeveloping cardiovascular disease, decreasing triglyceride or LDLcholesterol levels, decreasing blood pressure, decreasing pain orinflammation, treating diabetes, chronic pulmonary diseases (e.g.,asthma and chronic obstructive pulmonary disease), and irritable bowelsyndrome, and decreasing one or more symptoms of an autoimmune disease(e.g., multiple sclerosis and lupus erythematosus.

Pharmaceutical Compositions

The invention provides pharmaceutical compositions containing omega-3oils in a non-hydrophilic co-solvent system or kit that have increasedabsorption rates. The omega-3 oils included in the pharmaceuticalcompositions may be obtained from a natural source, including, forexample, cold water oily fish (e.g., salmon, tuna, herring, mackerel,anchovies, and sardines), pollock, cod, catfish, flounder, grouper,halibut, mahi mahi, orange roughy, red snapper, shark, swordfish,tilefish, plankton, algae, krill, green-lipped mussel, chia seeds,kiwifruit seeds, perilla seeds, flax seeds, lingonberry seeds, camelinaseeds, purslane seeds, black raspberry seeds, hemp seeds, butternut,walnuts, pecan nuts, and hazel nuts. The omega-3 oil included in thepharmaceutical compositions may be high grade (e.g., at least 70%, 75%,80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% pure). Inone example, the high grade omega-3 oil used in the pharmaceuticalcompositions is OmegaMaine omega-3 oils. In additional non-limitingexamples of the pharmaceutical compositions, the omega-3 oil is at least25% (e.g., at least 30%, 35%, 40%, 45%, 50%, 55%, 65%, 70%, 75%, 80%,85%, 90%, or 95%) of the composition's total mass. In one implementationof the invention, at least 10% (e.g., at least 15%, 20%, 25%, 30%, 35%,40%, 45%, or 50%) of the omega-3 oil in the composition is in solutionand at least 50% of the omega-3 oil in the composition is in stablesuspension form (e.g., at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,or 95%). The omega-3 oil is typically a mixture of one or more omega-3fatty acids, including EPA, DHA, or a combination thereof. The omega-3oil may contain an alkyl ester of a fatty acid (e.g., an alkyl ester ofeicosapentaenoic acid and docosahexanoic acid) or may be in the form offree fatty acids and/or triglycerides. In other embodiments, the omega-3oil is a mixture of triglycerides and free fatty acids.

The co-solvent in the pharmaceutical compositions may include one ormore (e.g., two, three, four, five, six, seven, eight, nine, or ten)solvents or agents that enhance the absorption rate of omega-3 oils in amammal (e.g., a human), including, but not limited to: herbal-based oil(e.g., rosemary oil, basil oil, turmeric oil, and ginger oil), vitaminE, medium chain triglycerides (MCTs), lecithin, phosphatidylcholine,glucosamine, ethanol, Tween surfactant (e.g., Tween-20, Tween-40,Tween-60, and Tween-80), phosphatidylserine, phosphatidylethanolamine,amides of intermediate (C-8 to C-12) fatty acids, amide of long chainfatty acids (C-13 to C-24), lauric alcohol, lauric acid,phosphatidylinositol, phosphatidic acid, natural fish oil, coconut oil,polytocopherol, sorbital laurate, and cremaphor. Suitable ingredientsare defined in Example 1 given below and by Formulas 1 and 2 withinExample 1. In non-limiting examples of the pharmaceutical compositions,the co-solvent is less than 30% (e.g., less than 25%, 20%, 15%, 10%, or5%) of the composition's total mass. In one example, the compositionscontains a herbal-based oil (1% to 10% or 3% to 5% of the composition'sfinal mass). In another example, the composition contains vitamin E(1.3% to 13.4% of the composition's final mass or 13.4 mg to 134 mg perdose).

The pharmaceutical compositions may further include one or more (e.g.,one, two, three, four, or five) nitric oxide-stimulating or -releasingagents. Non-limiting examples of such nitric oxide-stimulating or-releasing agents include: citrulline, arginine, di-arginine,nitroglycerin, organic nitrates (e.g., glyceryl trinitrate, isosobridedinitrate, and isosorbide-5-mononitrate), sodium nitroprusside,S-nitrosothiols (e.g., S-nitroso-N—N-acetylpenicillamine andS-nitrosoglutathione), sydnonimines (e.g., molsidomine and3-morpholino-sydnonimine), NONOates (e.g., spermine NONOate), andfuroxans.

The pharmaceutical compositions may further include one or more (e.g.,one, two, three, four, or five) therapeutic organic molecule(s). Forexample, the therapeutic organic molecules may have a molecular weightbetween 100 g/mole and 800 g/mole (e.g., between 100 g/mole and 400g/mole, between 400 g/mole and 800 g/mole, between 200 g/mole and 700g/mole, and between 300 g/mole and 600 g/mole), a log P value greaterthan 2 (e.g., greater than 2.5, greater than 3.0, greater than 3.5, andgreater than 4.0), and/or a melting point of below 200° C. (e.g., below180° C., below 160° C., and below 140° C.). Non-limiting examples oftherapeutic organic molecules that may be included in the pharmaceuticalcompositions include NSAIDs (e.g., naproxen sodium, diclofenac sodium,diclofenac potassium, aspirin, sulindac, diflunisal, piroxicam,indomethacin, ibuprofen, nabumetone, choline magnesium trisalicylate,sodium salicylate, salicylsalicylic acid, fenoprofen, flurbiprofen,ketoprofen, meclofenamate sodium, meloxicam, oxaprozin, sulindac,tolmetin, and COX-2 inhibitors (e.g., rofecoxib, celecoxib, valdecoxib,and lumiracoxib)) and DMARDs (e.g., auranofin, aurothioglucose,azathioprine, chlorambucil, cyclophosphamide, D-penicillamine, goldsodium thiomalate (injectable gold), hydroxychloroquine, leflunomide,methotrexate, minocycline, mycophenolate mofetil, and sulfasalazine).Additional examples of therapeutic organic molecules are known in theart (e.g., fenofibrate, statins, niacin, additional NSAIDs, andadditional DMARDs). More than one (e.g., two, three, four, or five) ofthe above compositions may be administered for additional therapeuticbenefit. Further, the NSAID class therapeutic may be combined with oneor more (e.g., two, three, four, or five) antihistamine(s) or one ormore (e.g., two, three, four, or five) antihistamine(s) that have H-1receptor antagonist properties. Non-limiting examples of H-1antihistamines include non-tricyclic antihistamines (e.g.,diphenhydramine and triprolidine) and tricyclic antihistamines (e.g.,doxepin and impramine). Non-limiting examples of compositions containingone or more therapeutic organic molecule(s) contain a Tween surfactant(e.g., Tween-80, Tween-60, Tween-40, and Tween-20) and ethanol.

In one example of a pharmaceutical composition according to theinvention, the non-hydrophilic co-solvent contains the combination of aherbal-based oil (e.g., rosemary oil, basil oil, turmeric oil, andginger oil), vitamin E (e.g., in purified or unpurified form (e.g.,polytocopherol)), medium chain triglycerides (e.g., in purified orunpurified form (e.g., coconut oil)), lecithin, and phosphatidylcholine(e.g., in purified or unpurified form (e.g., a natural lipidcomposition)). In this example, the herbal-based oil is at least 1% to5% of the composition's total mass (e.g., 2% to 4%), the amount ofvitamin E present in a single dose of the composition is between 13.4 mgto 134 mg (e.g., 40 mg to 120 mg, 50 mg to 100 mg, 15 mg to 60 mg, and60 mg to 134 mg), the MCTs are between 1% to 10% of the composition'stotal mass (e.g., between 1% and 5%, between 5% and 10%, between 2% and8%, between 3% and 7%, and between 4% and 6%), and thephosphatidylcholine is between 0.5% and 10% of the composition's totalmass (e.g., between 2% and 8%, between 3% and 7%, between 4% and 6%,between 1% and 5%, and between 5% and 10%). Additional examples ofpharmaceutical compositions are similar to this example, except thatthey further include in the co-solvent system a Tween surfactant (e.g.,Tween-80, Tween-60, Tween-40, and Tween-20) and/or ethanol (e.g.,absolute ethanol). Other examples of pharmaceutical compositions areidentical to the above examples specified in this paragraph, except thatthey further include in the non-hydrophilic co-solvent rosemary oiland/or glucosamine. Further examples of pharmaceutical compositions aresimilar to the above examples in this paragraph, except that theyfurther include one or more (e.g., one, two, three, or four) ofphosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, andphosphatidic acid (e.g., phosphatidylinositol and phosphatidic acid). Inany of the above examples in this paragraph, the pharmaceuticalcompositions may further include one or more (e.g., one, two, three,four, or five) nitric oxide-stimulating or -releasing agents (see,examples above) and/or one or more (e.g., one, two, three, four, orfive) therapeutic organic molecules, such NSAIDs (e.g., ketoprofen) orDMARDs (e.g., methotrexate).

Additional examples of the provided pharmaceutical compositions contain70% to 80% w/w of natural fish oil as a source of omega-3 oil, 5% to 15%w/w of coconut oil as a source of MCTs, 0.5% to 5% w/w of polytocopherolas a source of vitamin E, 1% to 10% w/w of absolute ethanol, 1% to 10%w/w of sorbitol laurate, and/or 1% to 10% w/w cremaphor. Anotherexample, of the composition contains 70% to 80% w/w natural fish oil assource of omega-3 oil, 5% to 15% w/w of coconut oil as a source of MCTs,0.5% to 5% w/w of polytocopherol as a source of vitamin E, 1% to 5% w/wof absolute ethanol, 1% to 10% w/w of sorbitol laurate, and/or 5% to 15%w/w cremaphor.

Further examples of the provided pharmaceutical compositions contain 65%to 75% w/w of natural fish oil as a source of omega-3 oil, 1% to 10% w/wcoconut oil as a source of MCTs, 0.5% to 5% w/w of polytocopherol as asource of vitamin E, 1% to 10% w/w of absolute ethanol, 1% to 10% w/w ofsorbitol laurate, 1% to 10% w/w cremaphor, and/or 1% to 10% w/w of oneor more (e.g., one, two, three, four, or five) therapeutic organicmolecule(s) (e.g., ketoprofen, methotrexate, fenofibrate, statin, and/orniacin or combinations thereof). In another example, the compositioncontains 65% to 75% w/w of natural fish oil as a source of omega-3 oil,1% to 10% w/w coconut oil as a source of MCTs, 0.5% to 5% w/w ofpolytocopherol as source of vitamin E, 1% to 5% w/w of absolute ethanol,1% to 10% w/w of sorbital laurate, 1% to 15% w/w cremaphor, and/or 1% to10% w/w of one or more (e.g., one, two, three, four, or five)therapeutic organic molecule(s) (e.g., ketoprofen, methotrexate,fenofibrate, statin, and/or niacin). For example, in a formulation ofomega-3 oil and 1% ethanol, the fenobibrate dose/unit volume of thepharmaceutical composition will typically be in the range of 5 mg/mL to20 mg/mL, more typically in the range of 10 mg/mL to 15 mg/mL. In thepresence of absorption enhancers, this dose may be further lowered by atleast 10% (e.g., by at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,55%, 60%, 65%, 70%, 75%, or 80%, or between 1 mg/mL to 10 mg/mL or 0.1mg/mL to 5 mg/mL). Lowering the dose of FDA-approved therapeutics willlower the side effect profile while maintaining therapeutic efficacy. Inthe case of statins, the dose range/unit dose would be between 1 mg/mLand 4 mg/mL in the pharmaceutical composition. The typical dose would bebetween 0.5 mg/mL and 2 mg/mL in the pharmaceutical composition. In thepresence of absorption enhancers this dose may be further lowered by atleast 10% (e.g., at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,60%, 65%, 70%, 75%, or 80%). Liquid formulation of these drugs and alldrugs in general will be less variable and more uniform becauseabsorption efficiency will be improved, allowing the amount of drugproduct administered for a given therapeutic effect to be reduced. Sideseffects related to dose strength should decrease because of thereduction in drug load.

A single dose of the provided pharmaceutical compositions may containgreater than 2.5 g (e.g., greater than 2.6 g, 2.7 g, 2.8 g, 2.9 g, 3.0g, 3.1 g, 3.2 g, 3.3 g, 3.4 g, 3.5 g, 3.6 g, 3.7 g, 3.8 g, 3.9 g, 4.0 g,4.1 g, 4.2 g, 4.3 g, 4.4 g, 4.5 g, 4.6 g, 4.7 g, 4.8 g, 4.9 g, or 5.0 g)combined of EPA and DHA. For example, a single dose of thepharmaceutical composition may contain greater than 2.5 g (e.g., greaterthan 2.6 g, 2.7 g, 2.8 g, 2.9 g, 3.0 g, 3.1 g, 3.2 g, 3.3 g, 3.4 g, 3.5g, 3.6 g, 3.7 g, 3.8 g, 3.9 g, 4.0 g, 4.1 g, 4.2 g, 4.3 g, 4.4 g, 4.5 g,4.6 g, 4.7 g, 4.8 g, 4.9 g, or 5.0 g) combined of EPA and DHA in avolume of at least 5.0 mL (e.g., at least 5.5 mL, 6.0 mL, 6.5 mL, 7.0mL, 7.5 mL, 8.0 mL, 8.5 mL, 9.0 mL, 9.5 mL, 10.0 mL, 10.5 mL, 11.0 mL,11.5 mL, 12.0 mL, 12.5 mL, 13.0 mL, 13.5 mL, 14.0 mL, 14.5 mL, or 15.0mL).

A single dose of the provided pharmaceutical composition may containbetween 0.1 mg and 2.0 g (e.g., between 0.1 mg and 1.5 mg, 0.1 mg and 1g, 0.1 mg and 750 mg, 1 mg and 650 mg, 1 mg and 550 mg, 1 mg and 500 mg,10 mg and 450 mg, 10 mg and 400 mg, 10 mg and 350 mg, 10 mg and 350 mg,and 10 mg and 250 mg) of each of the one or more (e.g., one, two, three,four, or five) therapeutic organic molecules (e.g., a NSAID (e.g.,ketoprofen), DMARD (e.g., methotrexate), fenofibrate, a statin, andniacin).

The compositions may be formulated using any known method, includingoral formulations such as a pill (e.g., bilayered or trilayered pill), afluid (e.g., suspension-based liquid or a multi-component clear liquid),a capsule, or a dietary supplement (e.g., a shake or bar). Thecompositions may also be formulated for intramuscular, intraocular,intranasal, subcutaneous, intraarterial, and intravenous administration.Desirable embodiments of the invention are formulated as a liquid oralcomposition. Such a liquid oral composition may be administered to asubject having dysphagia. An artisan may evaluate a matrix ofpossibilities to select the optimal formulation, which may be regardedas that solution that fully dissolves the drug product and provides thebest PK/PD profile upon animal/human testing.

Kits

The invention further provides kits containing one or more (e.g., 1, 2,3, 4, 5, 6, 7, 8, 9, or 10) of the pharmaceutical compositions describedherein. Desirably, the pharmaceutical compositions included in the kitsare formulated for oral administration. The kits may further containmaterials to aid in the administration of the pharmaceuticalcompositions (e.g., a syringe). The kits may contain one or more dosesof a pharmaceutical compositions provided by the invention. The kits mayfurther contain instructions for administering the pharmaceuticalcompositions to a subject having a cardiovascular disease, a propensityto develop a cardiovascular disease, diabetes (e.g., type I or type IIdiabetes), inflammation, pain, elevated triglyceride levels, elevatedblood pressure, chronic pulmonary disease (e.g., asthma and chronicobstructive pulmonary disease), irritable bowel syndrome, autoimmunedisease (e.g., multiple sclerosis and lupus erythematosus), and/orelevated LDL cholesterol levels.

The kits may also include additional one or more (e.g., two, three, orfour) additional compositions containing a DMARD, a NSAID, and/or anantihistamine (e.g., an H-1 receptor antihistamine). The instructionsmay indicate that the one or more additional compositions containing aDMARD and/or a NSAID are administered to the subject at the same time(co-administered) as the pharmaceutical compositions containing omega-3oils (described above) or may indicate that the one or more additionalcompositions containing a DMARD and/or NSAID are delivered afteradministration (e.g., within 1 minute, 5 minutes, 10 minutes, 15minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, or 12hours) of the pharmaceutical compositions containing omega-3 oilsdescribed herein. The kits desirably contain compositions formulated asa liquid for oral administration.

Methods of Formulation

The invention further provides methods for formulating an omega-3oil-containing pharmaceutical composition having an increased absorptionrate relative to omega-3 oil alone, requiring the step of combining anomega-3 oil (e.g., purified or in a natural form (e.g., natural fishoil)) with a non-hydrophilic co-solvent. The non-hydrophilic co-solventused to formulate the omega-3 containing pharmaceutical compositions maycontain one or more (e.g., one, two, three, four, five, six, seven,eight, nine, or ten) solvents or agents that enhance the absorption rateof omega-3 oils in a mammal (e.g., a human), including, but not limitedto: herbal-based oil (e.g., rosemary oil, basil oil, turmeric oil, andginger oil), vitamin E, medium chain triglycerides (MCTs), lecithin,phosphatidylcholine, glucosamine, ethanol, Tween surfactant (e.g.,Tween-20, Tween-40, Tween-60, and Tween-80), phosphatidylserine,phosphatidylethanolamine, amides of intermediate (C-8 to C-12) fattyacids, amides of long chain (C-12 to C-24) fatty acids, lauric alcohol,lauric acid, phosphatidylinositol, phosphatidic acid, natural fish oil,coconut oil, polytocopherol, sorbital laurate, and cremaphor. An amideof a medium chain or long chain fatty acid may be derived from anaturally-occurring amino acid (e.g., glycine, lysine, and alanine).

Also provided are methods for formulating a pharmaceutical compositioncontaining omega-3 oil and one or more (e.g., one, two, three, four, orfive) therapeutic organic molecules having an increased absorption raterelative to omega-3 oil alone or the one or more therapeutic organicmolecules alone, requiring the step of combining an omega-3 oil (e.g.,purified or in a natural form (e.g., natural fish oil)) and one or moretherapeutic organic molecules with a non-non-hydrophilic co-solvent(described above). In additional examples of this method, the one ormore therapeutic organic molecule(s) are first combined with theco-solvent (e.g., a co-solvent containing one or more of ethanol, aTween surfactant (e.g., Tween-80, Tween-60, Tween-40, and Tween-20),MCTs, vitamin E, and/or lecithin) to solubilize the one or moretherapeutic organic molecule(s), and then the omega-3 oil is added toform the pharmaceutical composition. In desirable embodiments of thesemethods, the resulting composition is a liquid that may be orallyadministered.

Methods of Treatment

The invention also provides methods for decreasing the likelihood ofdeveloping a cardiovascular disease, decreasing the triglyceride or LDLcholesterol levels, decreasing blood pressure, decreasing pain orinflammation, treating diabetes (e.g., type I diabetes, type IIdiabetes, or pre-diabetes), chronic pulmonary diseases (e.g., asthma andchronic obstructive pulmonary disease), or irritable bowel syndrome,reducing one or more symptoms of an autoimmune diseases (e.g., multiplesclerosis and lupus erythamatosus), or reducing one or more symptoms ofallergic conditions (e.g., seasonal allergies or seasonal rhinitis whereit is standard to administer an H-1 receptor antihistamine) in a subjectcomprising administering to the subject one or more (e.g., one, two,three, four, or five) of the pharmaceutical compositions describedherein.

Methods for the diagnosis and/or monitoring of cardiovascular disease,triglyceride and LDL cholesterol levels, high blood pressure, pain,inflammation, chronic pulmonary diseases (e.g., asthma and chronicobstructive pulmonary disease), autoimmune diseases (e.g., multiplesclerosis and lupus erythematosus), and diabetes are known in the art.For example, a physician may monitor and/or diagnose cardiovasculardisease based on the presentation of one or more of the followingsymptoms in a subject: shortness of breath, heart palpitations,increased heart rate, increased blood pressure, weakness, dizziness,nausea, sweating, atherosclerotic plaques in artery walls, elevatedlow-density lipoprotein (LDL) cholesterol levels (e.g., greater than 70mg/dL or greater than 100 mg/dL), decreased high-density lipoprotein(HDL) cholesterol levels (e.g., less than 50 mg/dL or less than 40mg/dL), and increased triglyceride levels (e.g., greater than 150 mg/dLor greater than 200 mg/dL). Triglyceride and LDL cholesterol levels inthe blood of a subject may be monitored using known laboratory tests(e.g., a lipid profile test). Pain may be monitored by a physician usingone or more pain score tests to quantify pain in a subject. Non-limitingexamples of such pain score tests include: Alder Hey Triage Pain Score,Brief Pain Inventory (BPI), Dallas Pain Questionnaire, Dolorimeter PainIndex (DPI), Faces Pain Scale-Revised (FPS-R), Face Legs Arms CryConsolability scale, McGill Pain Questionnaire (MPQ), DescriptorDifferential Scale (DDS), Neck Pain and Disability Scale (N PAD),Numerical 11 point box (BS-11), Numeric Rating Scale (NRS-11),Roland-Morris Back Pain Questionnaire, Wong-Baker FACES Pain RatingScale, and Visual Analog Scale (VAS). A physician may monitorinflammation by measuring one or more of the following symptoms in asubject: increased (e.g., by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, 60%, 70%, 80%, 90%, or 95%) COX-1 and/or COX-2activity, increased (e.g., by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, 60%, 70%, 80%, 90%, or 95%) white blood cell count,increased (e.g., by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 70%, 80%, 90%, or 95%) C-reactive protein, interleukin-6,and/or TNF-α levels, swelling, pain, and increased (e.g., by at least5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 80%,90%, or 95%) erythrocyte sedimentation rate. Diabetes may be monitoredand/or diagnosed by a physician based on the presentation of thefollowing symptoms: increased weight (obesity), decreased insulinabsorption or sensitivity (e.g., decrease by at least 5%, 10%, 15%, 20%,25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%), elevated blood glucoselevels (e.g., one or more blood glucose readings greater than 104mg/dL), and increased glycated hemoglobin levels (e.g., HbA_(1C) greaterthan 7.0%).

The methods of the invention may be used to treat or decrease thelikelihood of developing a cardiovascular disease. The provided methodsmay reduce the severity or duration (e.g., by at least 10%, 15%, 20%,25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, or even 100%) of one or more (e.g., one, two, three, four, or five)of the symptoms of cardiovascular disease or prevent the onset of one ormore (e.g., one, two, three, four, or five) of the symptoms ofcardiovascular disease (e.g., compared to severity, duration, and numberof symptoms observed in the subject prior to treatment or the severity,duration, and number of symptoms observed in a subject or patientpopulation not receiving treatment). Non-limiting examples of symptomsof cardiovascular disease include: shortness of breath, heartpalpitations, increased heart rate, increased blood pressure, weakness,dizziness, nausea, sweating, atherosclerotic plaques in artery walls,elevated low-density lipoprotein (LDL) cholesterol levels (e.g., greaterthan 70 mg/dL or greater than 100 mg/dL), decreased high-densitylipoprotein (HDL) cholesterol levels (e.g., less than 50 mg/dL or lessthan 40 mg/dL), and increased triglyceride levels (e.g., greater than150 mg/dL or greater than 200 mg/dL). In one example, the methods of theinvention may result in one or more of the following effects: at least a10% reduction (e.g., at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,55%, or 60%) in LDL cholesterol levels, at least a 10% increase (e.g.,at least a 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, or 60%) in HDLcholesterol levels, and/or at least a 10% decrease (e.g., at least 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%) in triglyceride levels(relative to these levels in a subject prior to treatment or theselevels in a subject or patient population not receiving treatment). Themethods for treating or decreasing the likelihood of developingcardiovascular disease may also result in a decrease (e.g., by at least5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,75%, 80%, 85%, 90%, 95%, or 100%) in nausea and/or esophageal reflux(e.g., decrease in severity, incidence, and/or periodicity) compared tothe amount of nausea and/or esophageal reflux observed in a patientadministered omega-3 oil alone.

The methods of the invention may allow for a decrease in the dosage ofone or more cardiovascular disease medications (e.g., diuretics,angiotensin-converting enzyme (ACE) inhibitors, beta blockers, bloodthinning medications (e.g., aspirin), statins, and fibrates) to thesubject. The methods of treating or decreasing the likelihood ofdeveloping cardiovascular disease further comprise the administration ofone or more additional cardiovascular disease medications to the subject(e.g., diuretics, angiotensin-converting enzyme (ACE) inhibitors, betablockers, blood thinning medications (e.g., aspirin), statins, andfibrates). Additional cardiovascular disease medications that may beco-administered with one or more of the provided pharmaceuticalcompositions are known in the art.

The methods of the invention may also decrease (e.g., by at least 5%,10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, or 80%) thetriglyceride and/or LDL cholesterol levels in a subject (e.g., comparedto the triglyceride or LDL cholesterol levels in the subject prior totreatment or the triglyceride or LDL cholesterol levels in a subject orpatient population not receiving treatment). For example, the methods ofthe invention may decrease the triglyceride levels in a subject to below250 mg/dL (e.g., below 240 mg/dL, 230 mg/dL, 220 mg/dL, 210 mg/dL, 200mg/dL, 190 mg/dL, 180 mg/dL, 170 mg/dL, 140 mg/dL, 130 mg/dL, 120 mg/dL,110 mg/dL, and 100 mg/dL). In addition, the methods of the invention maydecrease the LDL cholesterol levels in a subject to below 180 mg/dL(e.g., below 170 mg/dL, 160 mg/dL, and 150 mg/dL, 140 mg/dL, 130 mg/dL,120 mg/dL, 110 mg/dL, 100 mg/dL, 90 mg/dL, 80 mg/dL, or 70 mg/dL). Themethods for decreasing the triglyceride and/or LDL cholesterol levelsmay also result in a decrease (e.g., by at least 5%, 10%, 15%, 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or100%) in nausea and/or esophageal reflux (e.g., decrease in severity,incidence, and/or periodicity) compared to the amount of nausea and/oresophageal reflux observed in a patient administered omega-3 oil alone.

The methods of the invention may allow for a decrease in the dosage ofone or more (e.g., one, two, three, or four) LDL cholesterol- ortriglyceride-lowering medication(s) (e.g., statins, such asatorvastatin, lovastatin, pravastatin, simvastatin, fluvastatin, androsuvastatin) to the subject. The methods of decreasing triglycerideand/or LDL cholesterol levels may further include the administration ofone or more additional LDL cholesterol- or triglyceride-loweringmedications to the subject (e.g., statins, such as atorvastatin,lovastatin, pravastatin, simvastatin, fluvastatin, and rosuvastatin).Additional triglyceride- and/or LDL cholesterol-lowering medicationsthat may be co-administered with one or more of the providedpharmaceutical compositions are known in the art.

The methods of the invention may also be used to treat or reduce (e.g.,by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,70%, 75%, 80%, 85%, 90%, 95%, or 99%) one or more (e.g., one, two,three, four, or five) symptoms of diabetes (e.g., type I diabetes, typeII diabetes, and pre-diabetes) in a subject. For example, the methods ofthe invention may result in an increase (e.g., by at least 5%, 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 80%, 90%, or 95%) ininsulin absorption and/or insulin sensitivity, a decrease (e.g., by atleast 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%) inblood glucose levels in a subject or patient population having elevatedblood glucose (e.g., one or more blood glucose reading(s) greater than104 mg/dL), and a decrease (e.g., by at least 5%, 10%, 15%, 20%, 25%, or30%) in glycated hemoglobin levels in a subject or patient populationhaving increased glycated hemoglobin levels (e.g., HbA_(1C) greater than7.0%). The methods of the invention may also result in an increase(e.g., at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or60%) in the HDL cholesterol levels in a subject compared to the HDLcholesterol levels in the subject prior to treatment or the HDLcholesterol levels in a subject or patient population not receivingtreatment. In one example of these methods of treating or reducing theseverity of one or more symptoms of diabetes, the subject isadministered one or more pharmaceutical compositions of the inventioncontaining phosphatidylinositol and phosphatidic acid.

The methods of the invention may allow for a decrease in the dosage ofone or more diabetes medications (e.g., insulin (e.g., lys-pro orshort-acting insulin, intermediate-acting insulin, or long-actinginsulin), sulfonylureas, biguanides, alpha-glycosidase inhibitors,thiazolidinediones, and meglitinides) to the subject. The methods oftreating diabetes may further include the administration of one or morediabetes medications to the subject (e.g., insulin (e.g., lys-pro orshort-acting insulin, intermediate-acting insulin, or long-actinginsulin), sulfonylureas, biguanides, alpha-glycosidase inhibitors,thiazolidinediones, and meglitinides). Additional diabetes medicationsthat may be co-administered with one or more of the providedpharmaceutical compositions are known in the art.

The methods of the invention may also be used to decrease (e.g., by atleast 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,70%, 75%, 80%, 85%, 90%, 95%, or 99%) pain (e.g., acute pain or chronicpain) in a subject. For example, the methods of the invention may resultin a decrease (e.g., by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,45%, 50%, 55%, 60%, 70%, 80%, 90%, or 95%) in the pain score in one ormore pain score tests (e.g., Alder Hey Triage Pain Score, Brief PainInventory (BPI), Dallas Pain Questionnaire, Dolorimeter Pain Index(DPI), Faces Pain Scale-Revised (FPS-R), Face Legs Arms CryConsolability scale, McGill Pain Questionnaire (MPQ), DescriptorDifferential Scale (DDS), Neck Pain and Disability Scale (NPAD),Numerical 11 point box (BS-11), Numeric Rating Scale (NRS-11),Roland-Morris Back Pain Questionnaire, Wong-Baker FACES Pain RatingScale, and Visual Analog Scale (VAS)). The methods of the invention mayalso result in a decrease (e.g., by at least 5%, 10%, 15%, 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%)in the number of gastric lesions in a subject compared to the number ofgastric lesions observed when an NSAID and/or a DMARD are administeredalone. In one example of the methods for decreasing pain, the subject isadministered one or more pharmaceutical compositions of the inventioncontaining rosemary oil and glucosamine.

The methods of the invention may allow for a decrease in the dosage ofone or more anti inflammatory/analgesics (e.g., diclofenac, diflusinal,etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen,ketorolac, meclofenamate, mefenamic acid, meloxicam, nabumetone,naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin,celecoxib, buprenorphine, butorphanol, codeine, hydrocodone,hydromorphone, levorphanol, meperidine, methadone, morphine, nalbuphine,oxycodone, oxymorphone, pentazocine, propoxyphene, tramadol,acetaminophen, and aspirin) administered to the subject. The methods ofdecreasing pain may further include the administration of one or more(e.g., one, two, three, or four) analgesics to the subject (e.g.,diclofenac, diflusinal, etodolac, fenoprofen, flurbiprofen, ibuprofen,indomethacin, ketoprofen, ketorolac, meclofenamate, mefenamic acid,meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam,sulindac, tolmetin, celecoxib, buprenorphine, butorphanol, codeine,hydrocodone, hydromorphone, levorphanol, meperidine, methadone,morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propoxyphene,tramadol, acetaminophen, and aspirin). Additional analgesics that may beco-administered with one or more of the provided pharmaceuticalcompositions are known in the art.

The methods of the invention may also be used to decrease (e.g., by atleast 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,75%, 80%, 85%, 90%, 95%, or 99%) inflammation or one or more (e.g., one,two, three, four, or five) symptoms of inflammation in a subject. Forexample, the methods of the invention may result in a decrease (e.g., byat least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%,80%, 90%, or 95%) in COX-1 and/or COX-2 activity relative to the COX-1and/or COX-2 activity in the subject prior to treatment or the COX-1and/or COX-2 activity in a subject or patient population not receivingtreatment. The methods of the invention may also result in a decrease(e.g., by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,60%, 70%, 80%, 90%, or 95%) in white blood cell count relative the whiteblood cell count in the subject prior to treatment or the white bloodcell count in a subject or a patient population not receiving treatment.The methods of the invention may also result in a decrease (e.g., by atleast 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%,80%, 90%, or 95%) in C-reactive protein, interleukin-6, and/or TNF-alphalevels, swelling, and/or pain in a subject relative to the amount ofC-reactive protein levels, swelling, and/or pain observed in the subjectprior to treatment or the amount of C-reactive protein levels, swelling,and/or pain observed in a subject or a patient population not receivingtreatment. The methods of treatment may also result in a decrease (e.g.,by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%,70%, 80%, 90%, or 95%) in erythrocyte sedimentation rate in a subjectcompared to the erythrocyte sedimentation rate in the subject prior totreatment or the erythrocyte sedimentation rate in a subject or apatient population not receiving treatment. The provided methods mayalso result in a decrease (e.g., by at least 5%, 10%, 15%, 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%)in the number of gastric lesions in a subject compared to the number ofgastric lesions observed when an NSAID and/or a DMARD are administeredalone. In one example of the methods for decreasing inflammation, thesubject is administered one or more pharmaceutical compositions of theinvention containing rosemary oil or glucosamine.

The provided methods may allow for a decrease in dosage ofanti-histamine used in the treatment of allergies and generalinflammatory conditions. Decreasing the dosage of antihistamine willdecrease one or more of the side effects of the antihistamine class(e.g., sedation).

The provided methods may also allow for a decrease in the dosage of oneor more anti-inflammatory medications (e.g., NSAIDs) administered to asubject. The methods for decreasing inflammation may further include theadministration of one or more (e.g., one, two, three, or four)anti-inflammatory medications to the subject (e.g., one or more NSAIDs).Additional anti-inflammatory medications that may be co-administeredwith one or more of the provided pharmaceutical compositions are knownin the art.

The method of the invention may also be used to treat chronic pulmonarydisease (e.g., asthma and chronic obstructive pulmonary disease) andirritable bowel syndrome, or reduce one or more symptoms of anautoimmune disease (e.g., multiple sclerosis and lupus erythematosus) ina subject. For example, the methods may affect at least a 10% (e.g., atleast 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%,80%, 85%, 90%, or 95%) decrease in one or more (e.g., two, three, orfour) symptoms of a chronic pulmonary disease. Non-limiting examples ofsuch symptoms include lung inflammation, pain, reduced lung capacity,and bronchioaveolar constriction. The methods may affect at least a 10%(e.g., at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,70%, 75%, 80%, 85%, 90%, or 95%) decrease in one or more (e.g., two,three, or four) symptoms of a irritable bowel syndrome or an autoimmunedisease (e.g., asthma and lupus erythematosus). Non-limiting examples ofsymptoms of irritable bowel syndrome include intestinal pain ordiscomfort, intestinal inflammation or lesions, and diarrhea.Non-limiting examples of symptoms of autoimmune disease include pain(e.g., joint pain), inflammation, and loss of motor function.

The effectiveness of all the above methods of treatment may be measuredby a physician using methods known in the art. In the above methods, oneor more pharmaceutical compositions of the invention may be administeredco-extensively (overlapping bioactive periods) or non-extensively(non-overlapping bioactive periods). The combined amount of EPA and DHApresent in a single dose of the provided pharmaceutical agents may be atleast 2.5 g (e.g., at least 2.6 g, 2.7 g, 2.8 g, 2.9 g, 3.0 g, 3.1 g,3.2 g, 3.3 g, 3.4 g, 3.5 g, 3.6 g, 3.7 g, 3.8 g, 3.9 g, 4.0 g, 4.1 g,4.2 g, 4.3 g, 4.4 g, 4.5 g, 4.6 g, 4.7 g, 4.8 g, 4.9 g, 5.0 g, 5.1 g,5.2 g, 5.3 g, 5.4 g, 5.5 g, 5.6 g, 5.7 g, 5.8 g, 5.9 g, or 6.0 g) in avolume of at least 5.0 mL (e.g., at least 5.5 mL, 6.0 mL, 6.5 mL, 7.0mL, 7.5 mL, 8.0 mL, 8.5 mL, 9.0 mL, 9.5 mL, 10.0 mL, 10.5 mL, 11.0 mL,11.5 mL, 12.0 mL, 12.5 mL, 13.0 mL, 13.5 mL, 14.0 mL, 14.5 mL, or 15.0mL). In these methods, the one or more pharmaceutical compositions maybe administered with one or more (e.g., one, two, three, four, or five)additional therapeutic agents including, but not limited to, one or more(e.g., one, two, three, four, or five) NSAID(s), one or more (e.g., one,two, three, four, or five) DMARDS(s), one or more (e.g., one, two,three, four, or five) analgesics, one or more (e.g., one, two, three,four, or five) triglyceride- or LDL cholesterol-lowering agents (e.g.,statins), one or more (e.g., one, two, three, four, or five)cardiovascular disease medications (e.g., diuretics,angiotensin-converting enzyme (ACE) inhibitors, beta blockers, bloodthinning medications (e.g., aspirin), statins, and fibrates), or one ormore (e.g., one, two, three, four, or five) diabetes medications (e.g.,insulin (e.g., lys-pro or short-acting insulin, intermediate-actinginsulin, or long-acting insulin), sulfonylureas, biguanides,alpha-glycosidase inhibitors, thiazolidinediones, and meglitinides). Theone or more additional therapeutic agents may be co-administered withthe one or more pharmaceutical compositions provided by the invention(e.g., in the same or separate dosage forms). In additional examples ofthe provided methods, the one or more additional therapeutic agents areadministered following the administration of the one or more providedpharmaceutical compositions to the subject (e.g., within 5 minutes, 10minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 40 minutes, 50minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8hours, 9 hours, 10 hours, 11 hours, 12 hours, 1 day, 2 days, 3 days, 5days, and 1 week). In additional examples of the methods, the one ormore pharmaceutical compositions provided by the invention may beadministered following the administration of the one or more additionaltherapeutic agent(s) to the subject (e.g., within 5 minutes, 10 minutes,15 minutes, 20 minutes, 25 minutes, 30 minutes, 40 minutes, 50 minutes,1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9hours, 10 hours, 11 hours, 12 hours, 1 day, 2 days, 3 days, 5 days, and1 week). In these methods, the one or more pharmaceutical compositionsand the one or more additional therapeutic agents may be administeredco-extensively (overlapping bioactive periods) or non-extensively(non-overlapping bioactive periods).

The amount of one or more pharmaceutical compositions that may beadministered to a subject per dose may be between 0.1 mg and 6 g, 0.1 mgand 5 g, 0.1 mg and 4.5 g, 0.1 mg and 5.0 g, 100 mg and 5.0 g, 500 mgand 5.0 g, 1.0 g and 5.0 g, 2.0 g and 5.0 g, 3.0 g and 4.5 g, and 3.0 gand 4.0 g. The amount of the one or more therapeutic organic moleculesthat may be administered to a subject per dose may be between 0.1 mg and2.0 g (e.g., between 0.1 mg and 1.5 mg, 0.1 mg and 1 g, 0.1 mg and 750mg, 1 mg and 650 mg, 1 mg and 550 mg, 1 mg and 500 mg, 10 mg and 450 mg,10 mg and 400 mg, 10 mg and 350 mg, 10 mg and 350 mg, and 10 mg and 250mg). The amount of one or more additional therapeutic agents that may beco-administered to a subject may be between 0.1 mg and 2.0 g (e.g.,between 0.1 mg and 1.5 mg, 0.1 mg and 1 g, 0.1 mg and 750 mg, 1 mg and650 mg, 1 mg and 550 mg, 1 mg and 500 mg, 10 mg and 450 mg, 10 mg and400 mg, 10 mg and 350 mg, 10 mg and 350 mg, and 10 mg and 250 mg).

The one or more pharmaceutical compositions provided by the inventionand the one or more additional therapeutic agents may be administered toa subject once a day, twice a day, three times a day, four times a day,once a week, twice a week, three times a week, four times a week, fivetimes a week, six times a week, seven times a week, bi-weekly,tri-weekly, or monthly. For example, the one or more pharmaceuticalcompositions and the one or more additional therapeutic agents may beorally administered to a subject once, twice, three times, or four timesa day. The one or more pharmaceutical compositions and the one or moreadditional therapeutic agents may be administered via the same route ofadministration (e.g., oral administration) or via different routes ofadministration (e.g., oral and parenteral administration). The one ormore pharmaceutical compositions and the one or more additionaltherapeutic agents may be formulated for any known route ofadministration, including oral, intravenous, intraarterial, intraocular,intranasal, intramuscular, and subcutaneous administration. Thetherapeutically effective dose of the one or more pharmaceuticalcompositions and the one or more additional therapeutic agents may bedetermined by a skilled physician using methods known in the art.

EXAMPLES

The features and other details of the invention will now be moreparticularly described and pointed out in the following examplesdescribing preferred techniques and experimental results. These examplesare provided for the purpose of illustrating the invention and shouldnot be construed as limiting.

Example 1 Pharmaceutical Compositions Containing Omega-3 Oil

In order to increase the absorption efficiency of omega-3 oils inmammals (e.g., humans), a series of omega-3 compositions containing oneor more adsorption enhancers were developed. An example of apharmaceutical composition containing omega-3 oil with an increasedabsorption rate is shown below.

Formula I:

Weight Component Percentage Natural Fish Oil (25% to 38% combined EPAand DHA) 75%  Coconut Oil (medium chain triglyceride mix) 5%Polytocopherol (source of vitamin E) 1% Absolute Ethanol 5% Span 20, NF4% Cremaphor ELO, NF 10% 

An example of a pharmaceutical composition containing omega-3 oil and anadditional therapeutic organic molecule is shown below.

Formula II:

Weight Component Percentage Natural Fish Oil (25% to 38% combined EPAand DHA) 70%  Coconut Oil (medium chain triglyceride mix) 5%Polytocopherol (source of vitamin E) 1% Absolute Ethanol 5% Span 20, NF4% Cremaphor ELO, NF 5% One or more therapeutic organic molecule(s) 10% 

In the above formulas, the natural fish oil used as a source of omega-3oil may be a high grade omega-3 oil (e.g., OmegaMaine omega-3 oil).

The above compositions may also include one or more (e.g., one, two,three, four, or five) nitric oxide-stimulating or -releasing agent(s).The addition of one or more nitric oxide-stimulating or -releasingagent(s) may increase the blood flow in the omental arterial bloodsupply and help to facilitate the rapid transfer of omega-3 fatty acidsand/or the one or more additional therapeutic organic molecules to theplasma.

Example 2 The Provided Omega-3 Oil-Containing PharmaceuticalCompositions Demonstrate an Increased Rate of Absorption in Humans

Experiments were performed to determine the absorption rate of one ofthe pharmaceutical compositions provided herein (Formula I shown inExample 1). Six human volunteers were treated once a day for one monthwith a natural source of omega-3 oils containing 3.5 grams of EPA andDHA combined in a 10 mL dose (Group I). Eight human volunteers (Group 2)were treated once a day for one month with the composition of Formula I(shown above). For both groups, the starting omega-3 fatty acid contentin whole blood was between 0.6% and 1.1% (baseline of 0.8% for EPA andDHA in red blood cell fatty acids) (Table 1).

After one month of dosing on a daily basis, the omega-3 oil fatty acidcontent of EPA and DHA was measured in each volunteer (Table 1). Thesedata demonstrate that the absorption enhancers in Formula I result in a1.8-fold increase in the absorption of EPA and DHA in humans.

TABLE 1 % of EPA and DHA in White Treatment Blood Cell Fatty AcidsBaseline 0.8% Group I 3.8% Group II 6.8%

Example 3 Analyses of the Absorption Rate of Pharmaceutical CompositionsContaining Omega-3 Oil and an Additional Therapeutic Organic Molecule

Additional experiments to test the absorption rate of the differentomega-3 oil-containing pharmaceutical compositions described herein wasillustrated in a mouse model. In these experiments, mice (4/group) wereadministered 25 mg/kg ibuprofen in the composition of Formula II, in100% natural fish oil, or in saline. The time to reach C_(max) andT_(max) for ibuprofen was determined from mouse tail vein samples (Table2).

The data for this experiment show that natural fish oil is an absorptionenhancer and that a further increase in absorption rate and C_(max) isachieved when one or more additional absorption enhancers are used(e.g., the additional absorption enhancers in Formula II).

TABLE 2 Cmax T_(1/2) Ibuprofen in saline 10 μg/mL 60 min Ibuprofen inomega 3/Formula 2 14 μg/mL 35 min

Example 4 The Provided Pharmaceutical Compositions Containing Omega-3Oil and Ketoprofen Demonstrate Reduced Formation of Stomach Lesions inMice

A negative side effect of the administration of NSAIDs in humans is theformation of stomach lesions. Pharmaceutical compositions containingomega-3 oils and ketoprofen (described herein) were tested for theirability to induce gastric lesions in a mouse model. In theseexperiments, fasted mice were given 10 mg/kg ketoprofen. The ketoprofenwas administered in saline or in 100% fish oil. In a control experiment,mice were treated with natural omega-3 oil one-hour prior to ketoprofenadministration. One-hour after ketoprofen administration, the mice weresacrificed and their stomachs analyzed for lesions (Table 3).

TABLE 3 Average Lesions Treatment Score/Stomach Ketoprofen in Saline (n= 8) 33 Natural Omega-3 Oil Pretreatment (n = 8) 8 Ketoprofen in 100%Fish Oil (n = 8) 12

These data show that the administration of ketoprofen in one of thepharmaceutical compositions provided by the invention (100% fish oil)results in decreased formation of stomach lesions.

Example 5 Combination Therapy of Inflammation in a Mouse Model Using anOmega-3 Oil Pharmaceutical Composition

Experiments were performed to determine whether the administration ofketoprofen in combination with an omega-3 oil-containing pharmaceuticalcomposition would decrease inflammation in a mouse model(carrageenin-induced ear swelling mouse model). In these experiments,ketoprofen was administered in a dosage (2 mg/kg) that results in a 50%decrease in induced inflammation in this mouse model. Ketoprofen wasadministered alone or following pretreatment with omega-3 oil. Theamount of inflammation was determined by measuring the ear volume of thetreated mice compared to control mice not receiving ketoprofen (Table4). Eight mice were used for each treatment.

TABLE 4 Treatment % of Inhibition of Inflammation Pretreatment withOmega-3 Oil, 85% Followed by Ketoprofen Ketoprofen Only 45%

These data demonstrate that administration of an omega-3 oil-containingpharmaceutical composition prior to administration of ketoprofen resultsin an increased reduction in inflammation compared to the administrationof ketoprofen alone.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention; can makevarious changes and modifications of the invention to adapt it tovarious usages and conditions. Thus, other embodiments are also withinthe claims.

What is claimed is:
 1. A composition comprising omega-3 oil in anon-hydrophilic co-solvent comprising a herbal-based oil, vitamin E,medium chain triglycerides (MCTs), lecithin, and phosphatidylcholine. 2.The composition of claim 1, wherein said composition is formulated as aliquid.
 3. The composition of claim 1, wherein the omega-3 oil is from anatural source.
 4. The composition of claim 3, wherein the naturalsource is selected from the group consisting of: salmon, herring,mackerel, and sardines.
 5. The composition of claim 1, wherein theomega-3 oil is high grade.
 6. The composition of claim 5, wherein thehigh grade omega-3 oil is OmegaMaine omega-3 oils.
 7. The composition ofclaim 1, wherein the omega-3 oil is an alkyl ester of a fatty acid. 8.The composition of claim 1, wherein the omega-3 oil is an alkyl ester ofeicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), or a mixtureof EPA and DHA.
 9. The composition of claim 1, wherein the omega-3 oilsare in the form of triglycerides.
 10. The composition of claim 1,wherein the omega-3 oils are a mixture of triglycerides and free fattyacids.
 11. The composition of claim 2, wherein said compositions isformulated in a dose containing greater than 3.0 g combinedeicosapentaenoic acid and docosahexanoic acid per 10 mL.
 12. Thecomposition of claim 11, wherein said composition is formulated in adose containing greater than 3.0 g combined EPA and DHA per 10 mL. 13.The composition of claim 1, wherein said non-hydrophilic co-solvent isless than 30% of the composition's total mass.
 14. The composition ofclaim 1, wherein said herbal-based oil is 1% to 10% of the composition'stotal mass.
 15. The composition of claim 14, wherein said herbal-basedoil is 3% to 5% of the composition's total mass.
 16. The composition ofclaim 1, wherein the herbal-based oil is selected from the groupconsisting of rosemary oil, basil oil, turmeric oil, and ginger oil. 17.The composition of claim 14, wherein said herbal-based oil is rosemaryoil.
 18. The composition of claim 1, wherein the amount of vitamin Epresent in a single dose of said composition is between 13.4 to 134 mg.19. The composition of claim 1, wherein the amount of vitamin E presentis 1.3% to 13.4% of the composition's mass.
 20. The composition of claim1, wherein said MCTs are from coconut oil.
 21. The composition of claim1, wherein said MCTs are between 1% to 10% of the composition's totalmass.
 22. The composition of claim 21, wherein said MCTs are 5% of thecomposition's total mass.
 23. The composition of claim 1, whereinphosphatidylcholine is 0.5% to 10% of the composition's total mass. 24.The composition of claim 23, wherein said phosphatidylcholine is 2% to6% of the composition's total mass.
 25. The composition of claim 1,further comprising one or more nitric oxide-stimulating or -releasingagent(s).
 26. The composition of claim 25, wherein said nitricoxide-stimulating or -releasing agent is selected from the group ofarginine, a di-arginine, and citrulline.
 27. The composition of claim 1,further comprising glucosamine.
 28. The composition of claim 27, whereinsaid herbal-based oil is rosemary oil.
 29. The composition of claim 1,wherein said composition further comprises ethanol.
 30. The compositionof claim 1, wherein said composition further comprises a Tweensurfactant.
 31. The composition of claim 30, wherein said Tweensurfactant is selected from the group consisting of: Tween-80, Tween-60,Tween-40, and Tween-20.
 32. The composition of claim 31, wherein saidTween surfactant is Tween-80.
 33. The composition of claim 30, furthercomprising ethanol.
 34. The composition of claim 1, further comprisingone or more therapeutic organic molecule(s) with a molecular weightbetween 100 g/mole and 800 g/mole, a log P value greater than 2, or amelting point below 200° C.
 35. The composition of claim 33, furthercomprising one or more therapeutic organic molecule(s) with a molecularweight between 100 g/mole and 800 g/mole, a log P value greater than 2,or a melting point below 200° C.
 36. The composition of claim 35,wherein said therapeutic organic molecule is a non-steroidalanti-inflammatory drug (NSAID) or a disease-modifying anti-rheumaticdrug (DMARD).
 37. The composition of claim 35, wherein said therapeuticorganic molecule is fenofibrate, a statin, or niacin.
 38. Thecomposition of claim 37, wherein a dose of said composition contains 5mg/mL to 20 mg/mL fenofibrate.
 39. The composition of claim 38, whereinsaid dose contains 10 mg/mL to 15 mg/mL fenofibrate.
 40. The compositionof claim 37, wherein a dose of said composition contains 1 mg/mL to 4mg/mL of a statin.
 41. The composition of claim 40, wherein a dose ofsaid composition contains 0.5 mg/mL to 2 mg/mL of a statin.
 42. Thecomposition of claim 36, wherein said NSAID is selected from the groupconsisting of ketoprofen, ibuprofen, diflunisal, diclofenac, andnaproxen.
 43. The composition of claim 42, wherein said NSAID isketoprofen.
 44. The composition of claim 36, wherein said DMARD ismethotrexate.
 45. The composition of claim 36, wherein said herbal-basedoil is rosemary oil and said composition further comprises glucosamine.46. The composition of claim 35, wherein said therapeutic organicmolecule is an H-1 antihistamine.
 47. The composition of claim 46,wherein the H-1 antihistamine is from the tricyclic class ofantihistamines.
 48. The composition of claim 47, wherein the tricyclicantihistamine is imipramine or doxepin.
 49. The composition of claim 46,wherein the H-1 antihistamine is from the non-tricyclic class ofantihistamines.
 50. The composition of claim 49, wherein thenon-tricyclic antihistamine is diphenhydramine or triporlidine.
 51. Thecomposition of claim 1, further comprising one or more agents selectedfrom the group consisting of: phosphatidylserine,phosphatidylethanolamine, phosphatidylinositol, and phosphatidic acid.52. The composition of claim 51 comprising phosphatidylinositol andphosphatidic acid.
 53. The composition of claim 1, wherein 10% of theomega-3 oil is in solution and the remaining 90% of the omega-3 oil isin stable suspension form.
 54. The composition of claim 2, wherein saidcomposition is formulated for oral administration.
 55. A compositioncomprising: 70% to 80% w/w of natural fish oil as a source of omega-3oil; 5% to 15% w/w of coconut oil as a source of medium chaintriglycerides; 0.5% to 5% w/w polytocopherol as a source of vitamin E;1% to 10% w/w absolute ethanol; 1% to 10% w/w sorbital laurate; and 1%to 10% w/w cremaphor.
 56. A composition comprising: 70% to 80% w/w ofnatural fish oil as a source of omega-3 oil: 5% to 15% w/w coconut oilas a source of medium chain triglycerides; 0.5% to 5% w/w polytocopherolas a source of vitamin E; 1% to 5% w/w absolute ethanol; and 5% to 15%cremaphor.
 57. A composition comprising: 65% to 75% w/w of natural fishoil as a source of omega-3 oil; 1% to 10% w/w of coconut oil as a sourceof medium chain triglycerides; 0.5% to 5% w/w polytocopherol as a sourceof vitamin E; 1% to 10% w/w absolute ethanol; 1% to 10% w/w sorbitallaurate; 1% to 10% w/w cremaphor; and 1% to 10% w/w of a therapeuticorganic molecule.
 58. A composition comprising: 65% to 75% w/w ofnatural fish oil as a source of omega-3 oil; 1% to 10% w/w of coconutoil as a source of medium chain triglycerides; 0.5% to 5% w/wpolytocopherol as a source of vitamin E; 1% to 5% w/w absolute ethanol;1% to 10% w/w sorbital laurate; 1% to 15% w/w cremaphor; and 1% to 10%w/w of a therapeutic organic molecule. 59-142. (canceled)